Ca2+ homeostasis and intracellular cycling are critical to heart function. Myocardial sarcoplasmic reticulum (SR) Ca2+-ATPase (SERCA2a) and its negative regulator phospholamban (PLB) play dominant roles in lowering cytoplasmic calcium levels during cardiac relaxation and have been linked to delayed diastolic relaxation in failing hearts. This deterioration in Ca2+ cycling characteristic of heart failure (HF) in both animal models and humans has been associated with a reduction of SERCA2a activity and enhanced inhibition mediated by PLB. The current proposal is centered on these changes in cardiac dysfunction following myocardial infarction and the progression to heart failure. The proposal is formulated to learn whether adenoviral-mediated intracoronary delivery of a PLB-inhibitor to the myocardium of adult rabbits may alter SR signaling and function and attenuate the progression of ventricular dysfunction that accompanies HF. The Central Hypothesis is that SERCA2a and PLB are central figures contributing to the loss of SR-mediated Ca2+ uptake and eventual ventricular failure, and that myocardial gene transfer of a PLB inhibitor will preserve the activity of SERCA2a and improve the acute and chronic biochemical and physiological function of the infarcted heart.